The Vanilloid receptor 1 (VR1) is a ligand gated non-selective cation channel. It is believed to be a member of the transient receptor potential super family. VR1 is recognized as a polymodal nociceptor that integrates multiple pain stimuli, e.g., noxious heat, protons, and vanifloids (European Journal of Physiology 451:151-159, 2005). A major distribution of VR1 is in the sensory (Aδ- and C-) fibers, which are bipolar neurons having somata in sensory ganglia. The peripheral fibers of these neurons innervate the skin, the mucosal membranes, and almost all internal organs. It is also recognized that VR1 exists in bladder, kidney, brain, pancreas, and various kinds of organs. A body of studies using VR1 agonists, e.g., capsaicin or resiniferatoxin, have suggested that VR1 positive nerves are thought to participate in a variety of physiological responses, including nociception (Clinical Therapeutics. 13(3): 338-395, 1991, Journal of Pharmacology and Experimental Therapeutics 314:410-421, 2005, and Neuroscience Letter 388: 75-80, 2005). Based on both the tissue distribution and the roles of VR1, VR1 antagonists would have good therapeutic potential.
WO2005070929 discloses heterocyclic amine derivatives as vanilloid receptor ligands. WO2005070885 discloses amide derivatives useful as vanilloid receptor ligands. WO 2004069792 discloses quinoline-derived amide derivatives useful for prevention or treatment of e.g. inflammatory pain, burning pain, chronic obstructive pulmonary disease and osteoarthritis, are vanilloid receptor 1 modulators. WO 2003068749 discloses quinoline or isoquinoline carboxamide derivatives useful as antagonist of the vanilloid receptor (VR1). WO2005123688 discloses a variety of 3-aminoindazole derivatives as SGK-inhibitors for use in treatment of SGK-related diseases and illness such as diabetes, obesity and metabolic syndrome etc. WO2006051378 discloses a variety of N-sulfonylaminobenzyl-2-phenoxy amide derivatives as a modulator for vanilloid receptor. WO97/01539 discloses quinoline deridatives as melatonin conditions. WO2002/30426 discloses heteroaryl compounds as HIV integrase inhibitors. WO 2000073283 discloses heteroaryl compounds as metabotropic glutamate receptor antagonists. WO 2004014377 discloses heteroaryl compounds as matrix metalloproteinase inhibitors. WO 2005014533 discloses heteroaryl compounds as factor IX antagonists.
It would be desirable if there were provided improved VR1 selective antagonist with enhanced binding activity with the VR1 receptor by systemic administration and with a good half-life. Other potential advantages include less toxicity, good absorption, good solubility, low protein binding affinity, less drug-drug interaction, a reduced inhibitory activity at HERG channel, reduced QT prolongation and good metabolic stability.